PROJECT SUMMARY/ABSTRACT The growing prevalence of Alzheimer?s disease (AD) within an aging population has heightened the need to determine the etiologic and modifying factors that influence healthy brain aging and its shift to neuropathological processes such as AD. Aging of the human brain is a multifaceted, complex process that might be vulnerable to various changes/illnesses and is also the biggest risk factor for AD. An integrative approach to the study of brain aging is essential to better understand both healthy changes and neurodegenerative processes such as AD. A critical question is why do some individuals with AD develop cognitive symptoms earlier than others, even in the face of similar degrees of AD pathology? Also, why are certain brain regions more vulnerable to AD pathology than others? We believe that investigating brain metabolism, as a reflection of the demanding and dynamic physiology occurring in the brain throughout the lifespan, might provide key insights into these questions and of the pathophysiology of aging and AD in general. Our project is aimed at using brain metabolism to reveal sources of inter-individual differences that influence brain aging and the development and progression of AD. Simultaneous measurement of brain glucose uptake and oxygen utilization using positron emission tomography (PET) allows calculation of brain aerobic glycolysis (glucose metabolism in excess of oxidative phosphorylation or AG), which is a marker of synaptic plasticity and neuroprotection. Brain AG decreases with age and identifies regions subsequently targeted by AD pathology. In this project, we propose to combine our unique, multi-tracer PET imaging to evaluate how brain metabolism ? in particular AG ? relates to brain structure and cognition during healthy aging and in the preclinical and symptomatic stages of AD. Based on our PET measurements we will also calculate a ?metabolic brain age? and investigate its relationship with biological age and structural, functional and cognitive assessments. We will test our hypothesis that brain metabolism might predict aging-related changes in brain structure and function. We will evaluate whether inter-individual differences in brain metabolism correlate with inter-individual differences in cortical volume, connectivity and cognitive function. Our hypothesis is that low brain AG is associated with a more rapid appearance of imaging and cognitive features of AD. Conversely, high AG will be associated with increased resilience to the effects of brain aging and progression of AD. This project will thus establish the role of brain metabolism in determining what causes selective vulnerability of certain brain regions and individuals to aging and AD, and in doing so may provide an avenue to identify modifiable factors that influence the trajectory of brain aging and AD.